The present invention relates to an improved method and apparatus for detecting and diagnosing disease states in a living organism by using a plurality of electrical impedance measurements.
Methods for screening and diagnosing diseased states within the body are based on sensing a physical characteristic or physiological attribute of body tissue, and then distinguishing normal from abnormal states from changes in the characteristic or attribute. For example, X-ray techniques measure tissue physical density, ultrasound measures acoustic density, and thermal sensing techniques measures differences in tissue heat. Another measurable property of tissue is its electrical impedance; i.e., the resistance tissue offers to the flow of electrical current through it. Values of electrical impedance of various body tissues are well known through studies on intact humans or from excised tissue made available following therapeutic surgical procedures. In addition, it is well documented that a decrease in electrical impedance occurs in tissue as it undergoes cancerous changes. This finding is consistent over many animal species and tissue types, including, for example human breast cancers.
There have been a number of reports of attempts to detect breast tumors using electrical impedance imaging, such as, for example, U.S. Pat. No. 4,486,835. However, there are basic problems when trying to construct an image from impedance data. Electrical current does not proceed in straight lines or in a single plane; it follows the path of least resistance, which is inevitably irregular and three-dimensional. As a result, the mathematics for constructing the impedance image is very complex and requires simplifying assumptions that greatly decrease image fidelity and resolution.
A cancer, however, need not be xe2x80x9cseenxe2x80x9d to be detected; its presence can be detected by a marker associated with it, in this case a change in its electrical impedance, and a technique sensitive to the marker.
One technique for screening and diagnosing diseased states within the body using electrical impedance is disclosed in U.S. Pat. No. 6,122,544. In this patent data are obtained in organized patterns from two anatomically homologous body regions, one of which may be affected by disease. One subset of the data so obtained is processed and analyzed by structuring the data values as elements of an nxc3x97n impedance matrix. The matrices can be further characterized by their eigenvalues and eigenvectors. These matrices and/or their eigenvalues and eigenvectors can be subjected to a pattern recognition process to match for known normal or disease matrix or eigenvalue and eigenvectors patterns. The matrices and/or their eigenvalues and eigenvectors derived from each homologous body region can also be compared, respectively, to each other using various analytical methods and then subject to criteria established for differentiating normal from diseased states.
The present invention is directed to an improved method and apparatus for detecting and diagnosing disease states in a living organism by using a plurality of electrical impedance measurements. Although the present invention can be applied to any two homologous body regions, the application discussed scans for the presence or absence of breast abnormalities, and particularly benign and malignant tumors. While not intending to be bound by any particular theory, the method of the invention may arise from the following assumptions and hypotheses:
1. The tumor or tumors will occur either in only one breast, or if in both, at different homologous locations;
2. Both breasts are structurally similar, and therefore can be expected to be approximate mirror images (homologous) with respect to their impedance characteristics;
3. If impedance measurements are taken in a multiplicity of directions or paths across the breast (called an impedance scan in the present application), the presence of tumors, which are known to have a significantly lower impedance than the normal tissue they replace, will distort or change the impedance in at least some of the paths of current flow;
4. The magnitude of decreased impedance is greater for malignant tumors than for benign ones, providing a method for differentiating between these tumor types; and
5. There will always be some differences in impedance between breasts in a normal individual; but these differences will be less than the differences when a cancer is present.
The methodology of the present invention is implemented by a data acquisition and analysis apparatus that was developed for the special requirements of the invention. An improved breast electrode array is also provided of a design and construction that allows excellent conformability of the array to a breast surface and precise positioning of electrodes. This ensures that the multiplicity of positions that impedance measurements are obtained from in a first body part correspond as precisely as possible to the multiplicity of positions that measurements are obtained from in another, homologous, second body part. The apparatus has a number of innovations that provide rapid, accurate impedance measurements from a large number of electrode combinations, and virtually immediate data analysis and display. Impedance data are obtained in organized patterns from two anatomically homologous body regions, one of which may be affected by disease.
In one embodiment of the invention, electrodes are selected so that the impedance data obtained can be considered to represent elements of an nxc3x97n impedance matrix. Then two matrix differences are calculated to obtain a diagnostic metric from each. In one, the absolute difference between homologous right and left matrices, on an element-by-element basis, is calculated; in the second, the same procedure is followed except relative matrix element difference is calculated.
In another embodiment of the invention, the differences between corresponding impedance readings in the two body parts are compared in variety of ways that allow the calculation of metrics that can serve either as an indicator of the presence of disease or localize the disease to a specific breast quadrant or sector. Impedance differences are also displayed in a circular pixel plot in a representation of the frontal plane of the breast in this disclosure, although other shape plots in the same or other planes could effectively be produced with suitable choice of electrode geometry and positioning. The use of impedance differences subtracts out a voluminous and complex amount of impedance data produced by irregular, three-dimensional current paths, since under generally normal circumstances, the paths can be expected to be substantially identical in both body parts. Remaining differences are assumed to be due to disease states, and are much more manageable analytically.
Whereas the illustrated example of the present invention is a novel and improved method and apparatus for detecting and locating breast cancers, the invention can also be applied to other diseases or conditions in which there is a distinguishable difference in electrical impedance in the tissue as a result of the disease or condition. The present invention can also be used for detecting and locating diseases or conditions in any region of the body in which the electrical impedance of the region containing the disease or condition can be compared to an essentially identical, normal body region; for example, right and left forearms, right and left thighs, or right and left calves. Moreover, the present invention can be used to detect and locate diseases or conditions in any region of the body in which the electrical impedance of the region containing the disease or condition can be compared to another normal body region that, while not entirely identical, is consistently and constantly different; for example, right and left sides of the abdomen. In other words, the differences between the two regions being compared is a known constant in a healthy person and therefore can be subtracted out when performing a comparison.
In particular, this invention provides for an electrode array for diagnosing the presence of a disease state in a living organism, wherein the electrode array comprises a flexible body, a plurality of flexible arms extending from the body, and a plurality of electrodes provided by the plurality of flexible arms, wherein the electrodes are arranged on the arms to obtain impedance measurements between respective electrodes. In a preferred embodiment the plurality of flexible arms are spaced around the flexible body and are provided with an electrode pair.
Moreover, the flexible body of the electrode array can be provided with a stiffening member adapted to flatten part of the tissue of the living organism being diagnosed. In a preferred embodiment of the invention, the stiffening member is in the form of a ring and includes adhesive for fixation to the skin.
Further, each electrode of the electrode array can comprise an adhesive for fixation to the skin. In a preferred embodiment the adhesive is hydrogel. In another embodiment the adhesive is a gel foam pad, and particularly a gel foam pad in the form of a well that is filled with hydrogel.
The electrode array can also include means extending at least partially between the electrodes to at least partially electrically isolate the electrodes from each other. In a preferred embodiment the means comprises a ground conductive path. Moreover, the plurality of electrodes can comprise electrode pairs with each electrode pair having a current electrode and a voltage electrode. In this embodiment, the ground conductive path can extend at least partially between the current electrode and voltage electrode. Further, each electrode is connected to an associated terminal by a conductive path and the ground conductive path can extend at least partially between the conductive paths and associated terminals of respective electrodes to at least partially electrically isolate the conductive paths and the terminals from each other.
A method of forming an electrode array from a plurality of electrode array elements is also disclosed. Each electrode array element comprises a body having at least one arm extending from the body with at least one electrode provided on the arm. The method comprises:
a) overlying the plurality of electrode array elements at the respective bodies thereof to form a main body of the electrode array with the arms of the respective electrode array elements extending from the main body in spaced relation; and
b) clamping the plurality of electrode array elements together.
An alignment means can be provided to ensure that the arms of the respective electrode array elements extend around the main body of the electrode array in spaced relation. Moreover, a retaining member is used to clamp the plurality of electrode array elements together, and the retaining member can comprise a stiffening member.
This invention also provides a method of confirming whether an electrode array for use in diagnosing a part of a living organism has been properly connected to an electronic module. The electrode array includes a conductive path and a connector to link the conductive path to the electronic module. The method comprises attaching the conductive path to a terminal of the connector, connecting the electrode array to the electronic module using the connector, and testing whether the conductive path is properly connected to the terminals of the connector. In the embodiment disclosed the conductive path is a ground loop.
This invention also provides for a template for positioning an electrode array on a part of a living organism to be diagnosed for the presence of a disease state. The template comprises a body having a plurality of spaced parallel lines, and at least two alignment marks positioned on the plurality of spaced parallel lines. The body can be comprised of a flexible and transparent material. Moreover, the body can be elongate in a direction perpendicular to the parallel lines and have at least one line extending perpendicular to the parallel lines. The template preferably has at least two alignment marks positioned on the line extending perpendicular to the parallel lines. The body of the template can present an opening through which at least a portion of the part of the living organism to be diagnosed is visible. The alignment marks can be spaced around the opening.
A method of positioning an electrode array on a part of a living organism using the template is also disclosed. The method comprises:
a) marking the living organism on or near the part to be diagnosed with a line;
b) placing the positioning template on the part to be diagnosed and aligning at least one of the spaced parallel lines to the line marked on the living organism;
c) marking on the living organism the location of the alignment marks of the template; and
d) positioning the electrode array on the part to be diagnosed by aligning its corresponding alignment marks to the markings on the living organism from the template.
The invention also discloses a connecting member for connecting the electrode array to a connector that electrically links the electrode array to an electronic module. The connector member comprises a retaining member to receive the electrode array and connector in electrical contact with respect to one another, and a clamping member to clamp the electrode array and connector together and secure the electrical contact therebetween. The clamping member comprises a compressive member to apply a compressive force to the electrode array and connector. The retaining member comprises a base and a projection extending from the base over which a portion of the electrode array and connector can fit. The clamping member can further include a washer to fit over the projection of the retaining member and engage the electrode array and connector. The base of the retaining member can include at least one ridge extending from the base to engage the electrode array and connector on the opposite side from the washer. In the preferred embodiment the projection is a threaded tube and the compressive member is a fastening nut. Moreover, the base can further comprise alignment pins to ensure that the electrode array and connector are in correct electrical contact with respect to one another.
The washer can be provided with at least one channel adapted to fit therewithin the respective concentric ridges extending from the base. In one of the embodiments disclosed the washer is provided with at least two channels with each channel adapted to fit therewithin at least one of the ridges extending from the base. In another embodiment the washer is provided with at least two concentric ridges spaced to fit the respective concentric ridges extending from the base therebetween.
A method of connecting the electrode array to the connector that electrically links the electrode array to the electronic module is also disclosed. The method comprises:
a) placing the electrode array and connector in electrical contact with respect to one another; and
b) clamping the electrode array and connector together to secure the electrical contact therebetween.
Moreover, a method of minimizing the number of connections in a conductive path of the electrode array and the connector is disclosed. The method comprises:
a) providing a plurality of spaced unlinked conducting surfaces on the electrode array;
b) providing a plurality of spaced unlinked conducting surfaces on the connector, with two of the conducting surfaces selected to be connected to the conductive path; and
c) placing the electrode array and connector in electrical contact with respect to one another by overlapping the spaced unlinked conductive surfaces of the electrode array with the spaced unlinked conductive surfaces of the connector to form a continuous conductive path between the two selected conducting surfaces.
In a preferred embodiment the spaced unlinked conducting surfaces on the electrode array are spaced generally around an opening provided by the array, and the spaced unlinked conducting surfaces on the connector are spaced around a similar opening provided by the connector. The two selected conducting surfaces of the connector are adjacent to one another and a gap is provided in the spacing of the unlinked conducting surfaces of the electrode array so that when the electrode array and connector are placed in overlapping relation the gap is positioned with respect to the adjacent selected conducting surfaces of the connector so that the continuous path does not extend directly therebetween. In the preferred embodiment an alignment means is provided to ensure that the electrode array and connector overlie to form a continuous conductive path between the two selected conducting surfaces. Moreover, in the embodiment disclosed the conductive path is a ground conductive path.
Further, a method is disclosed for confirming an operable electrical contact between a plurality of spaced unlinked conducting surfaces of an electrode array and a plurality of spaced unlinked conducting surfaces of a connector. The method comprising:
a) placing the electrode array and connector in electrical contact with respect to one another by overlapping the spaced unlinked conductive surfaces of the electrode array with the spaced unlinked conductive surfaces of the connector to form a continuous conductive path between two selected conducting surfaces; and
b) measuring a test signal over the conductive path between the two selected conducting surfaces to see if an operable electrical contact has been established.
In the embodiment disclosed the conductive path is a ground conductive path and electrical resistance is measured and compared to a pre-established value for an operable electrical contact. Moreover, placing the electrode array and connector in electrical contact with respect to one another places respective terminals for electrodes of the electrode array into electrical contact with respective conductive surfaces of the connector. The test establishes whether proper electrical contact between the respective terminals and conductive surfaces has been established.
Further, this invention discloses apparatus for obtaining and processing impedance measurements from an electrode array comprising means to connect the apparatus to the electrode array (for example, a multiplexer), means to control the connection means to produce a sequence of impedance measurements (for example, a multiplexer controller), computer means to control the sequence controlling means, and means connected to the computer means to display the impedance measurements and any analyses thereof. In a preferred embodiment the apparatus further comprises at least one EEPROM chip containing a selection pattern to produce the sequence of impedance measurements and a counter to sequence the multiplexer through the set of impedance measurements. The display can comprise display screen to provide monitoring of the impedance measurements and analyses thereof, or a printer for hard copy of the impedance measurements and analyses thereof.
In the embodiment disclosed each impedance measurement is displayed as a grid element. Means are provided to identify the corresponding electrodes of the electrode array used to obtain the impedance measurement represented by a given grid element. Moreover, the identifying means can be used to provide a value of the impedance measurement represented by the grid element. In addition, the display can be provided with means to indicate that the value of the impedance measurement represented by the grid element does not correspond to a predetermined expected value.
A method of testing a multiplexer of this invention using two substantially identical multiplexers is also disclosed. The method reversely operates one of the multiplexers. The method comprises:
a) connecting the respective outputs of the two multiplexers to one another;
b) providing a calibration load to the input of the reversely operating multiplexer;
c) simultaneously controlling operation of the two multiplexers through a sequence of identical output selections; and
d) measuring the calibration load through the input of the normally operating multiplexer.
In particular, the measurement of the calibration load is an impedance measurement.
This invention also provides for a number of methods for diagnosing the possibility of a disease state in one of first and second substantially similar parts of a living organism. One method comprises:
a) obtaining a plurality of impedance measurements across predetermined portions of each of the parts to produce first and second sets of impedance measurements, the first set for the first part and the second set for the second part, and wherein each measurement of the first set has a corresponding measurement in the second set when taken across corresponding portions of each of the parts;
b) identifying the set with a lower mean impedance value;
c) creating an absolute difference set by subtracting each measurement of the set with the lower mean impedance value from the corresponding measurement of the other set; and
d) analyzing the absolute difference set to diagnose the possibility of a disease state.
In the embodiment disclosed each of the first and second sets are arranged in respective mathematical matrices, and the absolute difference set is an absolute difference matrix. The absolute difference matrix can be used to calculate a matrix norm that is compared to a pre-established threshold to diagnose the possibility of a disease state. The absolute difference matrix can also be used to calculate a matrix determinant that is compared to a pre-established threshold to diagnose the possibility of a disease state. Moreover, a sum of all of the elements in the absolute difference matrix can be calculated and compared to a pre-established threshold to diagnose the possibility of a disease state.
A visual display for diagnosing the possibility of a disease state and its location can also be provided by obtaining a sum of the values in each of the absolute difference matrix columns, then representing these sums in a graph, for example, as bar heights in a 2D graph. Another visual display can be obtained for diagnosing the possibility of a disease states and its location by plotting the value of each element in the absolute difference matrix as a function of the location of the value in the matrix. Such a plot can be in 3D.
Another method of diagnosing the possibility of a disease state in one of first and second substantially similar parts of a living organism comprises:
a) obtaining a plurality of impedance measurements across predetermined portions of each of the parts to produce first and second sets of impedance measurements, the first set for the first part and the second set for the second part, and wherein each measurement of the first set has a corresponding measurement in the second set when taken across corresponding portions of each of the parts;
b) creating a relative difference set by calculating the relative differences between each measurement from the first set with the corresponding measurement of the second set; and
c) analyzing the relative difference set to diagnose the possibility of a disease state.
Again, each of the first and second sets can be arranged in respective mathematical matrices, and the relative difference set is an relative difference matrix. The relative difference matrix can be used in a similar manner as the absolute difference matrix to diagnose the possibility of a disease state.
A further method comprises:
a) obtaining a plurality of impedance measurements across predetermined portions of each of the parts to produce first and second sets of impedance measurements, the first set for the first part and the second set for the second part, and wherein each measurement of the first set has a corresponding measurement in the second set when taken across corresponding portions of each of the parts;
b) calculating an impedance range by subtracting the minimum impedance measurement from either of the first and second sets from the maximum impedance measurement from such sets;
c) creating a plurality of numbered bin by subdividing the impedance range into smaller range sizes, then numbering the smaller range sizes consecutively;
d) assigning a bin number to each of the impedance measurements from the first and second sets;
e) creating a bin difference set by subtracting the bin number of each impedance measurement from one of the first and second sets from the bin number of each corresponding impedance measurement of the other set; and
f) analyzing the bin difference set to diagnose the possibility of a disease state.
In this method, a sum of all of the bin difference values in the bin difference set is calculated and compared to a pre-established threshold to diagnose the possibility of a disease state.
A similar method comprises:
a) obtaining a plurality of impedance measurements across predetermined portions of each of the parts to produce first and second sets of impedance measurements, the first set for the first part and the second set for the second part, and wherein each measurement of the first set has a corresponding measurement in the second set when taken across corresponding portions of each of the parts;
b) calculating a first impedance range for the first set by subtracting the minimum impedance measurement from the maximum impedance measurement of that set, and calculating a second impedance range for the second set by subtracting the minimum impedance measurement from the maximum impedance measurement of that set;
c) creating a plurality of first numbered bins by subdividing the first impedance range into a first set of smaller range sizes, then numbering the first set of smaller range sizes consecutively, and creating a plurality of second numbered bins by subdividing the second impedance range into a second set of smaller of range sizes, then numbering the second set of smaller range sizes consecutively;
d) assigning one of the first bin numbers to each of the impedance measurements from the first set, and assigning one of the second bin numbers to each of the impedance measurements from the second set;
e) creating a bin difference set by subtracting the bin number of each impedance measurement from one of the first and second sets from the bin number of each corresponding impedance measurement of the other set; and
f) analyzing the bin difference set to diagnose the possibility of a disease state.
In the embodiment disclosed a sum of all of the bin difference values in the bin difference set is calculated and compared to a pre-established threshold to diagnose the possibility of a disease state.
Yet a further method of diagnosing the possibility of a disease state in one of first and second substantially similar parts of a living organism comprises:
a) obtaining a plurality of impedance measurements taken between a predetermined plurality of points encircling the parts to produce first and second sets of impedance measurements, the first set for the first part and the second set for the second part, and wherein each measurement of the first set has a corresponding measurement in the second set when taken between a corresponding plurality of points;
b) assigning a bin number to each of the impedance measurements from the first and second sets;
c) producing a bin chord plot for each of the parts by graphically depicting the plurality of points as nodes on an encircling path for each part and the impedance measurements taken between the plurality of points as a chord extending between the respective nodes;
c) dividing each graphical depiction encircling each part into sectors; and
d) analyzing the bin chords that converge on a given node within a sector to diagnose the possibility of a disease state.
In the embodiment disclosed each sector graphically displays the total number of bin chords that converge on all the nodes included within that sector. Moreover, in the preferred embodiment the difference between corresponding bin chords for each part is plotted as a bin difference chord on the graphical depiction for the part having a lower bin number. The calculation of the number of bin difference chords that converge on a given node is then weighted depending on the differences between bin numbers from the first set and corresponding bin numbers from the second set.
Yet a further method of diagnosing the possibility of a disease state in one of first and second substantially similar parts of a living organism is disclosed. The method comprises:
a) obtaining a plurality of impedance measurements taken between a predetermined plurality of points encircling the parts to produce first and second sets of impedance measurements, the first set for the first part and the second set for the second part, and wherein each measurement of the first set has a corresponding measurement in the second set when taken between a corresponding plurality of points;
b) producing a pixel grid from a chord plot produced by the impedance measurements taken between the plurality of points; and
c) analyzing the pixel grid to diagnose the possibility of a disease state.
For this method the intensity of a pixel in the pixel grid is determined from the chords that pass through the pixel, i.e., by the number of chords that pass through the pixel, the size of the segments of the chords that pass through the pixels, and the impedance values of the chords that pass through the pixels. The intensity of the pixels can be equalized to account for differences in the number of chords that can pass through the various pixels and the size of the segments of the chords that pass through the pixels. Once equalized the pixel intensity indicates only impedance value.
Moreover, a pixel difference set can be created by subtracting the pixel impedance value from one of the first and second sets from the pixel impedance value of each corresponding pixel of the other set. In this method, a sum of all of the difference values in the pixel difference set is calculated and compared to a pre-established threshold to diagnose the possibility of a disease state.
The intensity of the pixels is displayed visually and can be generated by a computer to produce a plurality of levels that represent different impedance values. In a preferred embodiment the visual display generated by the computer has 256 intensity levels for representing different impedance values.
The pixel grid can be a pixel algebraic difference plot derived by subtracting corresponding impedance pixel measurements taken between the plurality of points of the first part and the second part. Further, the pixel grid can be a pixel relative difference plot derived by calculating the relative difference between corresponding impedance pixels from the plurality of points of the first and second part.
Further, for either pixel algebraic difference plots or for pixel relative difference plots the range of pixel impedance intensity can be scaled with a scale factor, derived for algebraic difference plots and for relative difference plots, pre-established such that the scale factor for the respective plot types, when applied to a subject having maximum observed pixel difference, would result in the maximum pixel intensity level of 256.
Yet further, for either pixel algebraic difference plots or for pixel relative difference plots the pixel grid can be divided into sectors with each sector graphically displaying the sum of the impedance values for all pixels that are within the sector.